Background: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in reproductive age women. Metabolic syndrome (MetS), a constellation of cardiometabolic risk factors, is a major health problem with a high prevalence in young women with PCOS (20-40%). Surprisingly, there is no consensus on the optimal treatment of overweight/obese women with PCOS not attempting pregnancy, resulting in conflicting clinical guidelines and prescribing patterns for the use of oral contraceptive pills (OCP) and metformin in the long term treatment of PCOS. Although OCP improve menstrual irregularity and lower androgens, they may be associated with increase in weight, serum triglycerides levels and blood pressure. In the OWL-PCOS study, we recently found that these adverse metabolic effects of OCP are exacerbated in overweight/obese women with PCOS. Metformin on the other hand, has a favorable metabolic profile but is less effective in improving menstrual regularity and reducing androgens. This conundrum highlights the need to identify comprehensive and safe treatments, whilst improving the metabolic profile in this high risk population. Specific Aims and Methods: In Specific Aim 1 we propose a pragmatic randomized clinical trial (COMET- PCOS) to compare the effects of OCP versus metformin versus OCP+metformin on change in prevalence of MetS after 6 months treatment in 240 overweight/obese women with PCOS. Based on our data from OWL- PCOS, we hypothesize that low dose OCP use will significantly increase the risk of MetS, while metformin alone or metformin+OCP use will result in a decrease or modest increase in MetS respectively. Our secondary aims will examine innovative mechanistic pathways associated with individual components of MetS. For example, to precisely understand the paradoxical effects of OCP on dyslipidemia (increased serum triglycerides and HDL-C levels), the commonest metabolic abnormality in PCOS, we will assess HDL-C function by measuring reverse cholesterol efflux, and lipoprotein particle size and number by NMR spectroscopy. In Specific Aim 2 we will precisely define the impact of OCP (by decreasing androgens) and metformin (by improving insulin sensitivity) or both on change in visceral fat distribution, glucose tolerance, inflammatory cytokines and adipokines. Summary: The presence of both PCOS and MetS adds significantly to long term morbidities, financial and emotional burden in young women. Our well-designed and adequately powered study will likely provide evidence favoring the use of OCP+metformin combination and avoiding use of OCP alone in management of overweight/obese women with PCOS. These findings will significantly change current clinical practice which is based on patient and physician preferences. Further, our secondary aims will be innovative as they are targeted at specifically comparing and understanding the pathophysiology of the metabolic alterations associated with use of OCP and metformin.